This invention relates to the use of an angiotensin II receptor antagonist, such as substituted imidazole compounds, for the treatment of Post-transplant hypertension. The invention also relates to use of an angiotensin II receptor antagonist, such as substituted imidazole compounds, for the preparation of drugs to increase the survival rate of transplant patients, including renal transplant patients. The invention also relates to a method of using an angiotensin II receptor antagonist, such as substituted for increasing the survival rate of transplant patients, including renal transplant patients.
Substituted imidazoles of formula I are known to inhibit the action of the octapeptide hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma xcex12-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causitive agent, for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds disclosed in this application inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. The present application discloses a method for the improvement of insulin sensitivity by administering an angiotensin II receptor antagonist, such as a substituted imidazole of formula I, to a species of mammal with hypertension due to angiotensin II. Administration of an angiotensin II receptor antagonist, such as a substituted imidazole of formula I, with a diuretic, such as furosemide or hydrochlorothiazide; either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensive effect of the compound, while also improving the insulin sensitivity of the patient.
K. Matsumura, et al., in U.S. Pat. No. 4,207,324 issued Jun. 10, 1980, discloses 1,2-disubstituted-4-haloimidazole-5-acetic acid derivatives of the formula: 
wherein R1 is hydrogen, nitro or amino; R2 is phenyl, furyl or thienyl optionally substituted by halogen, lower alkyl, lower alkoxy or di-lower alkylamino; R3 is hydrogen or lower alkyl and X is halogen; and their physiologically acceptable salts. These compounds have diuretic and hypotensive actions.
Furukawa, et al., in U.S. Pat. No. 4,355,040 issued Oct. 19, 1982, discloses hypotensive imidazole-5-acetic acid derivatives having the formula: 
wherein R1 is lower alkyl, cycloalkyl, or phenyl optionally substituted; X1, X2, and X3 are each hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy, Y is halogen and R2 is hydrogen or lower alkyl; and salts thereof.
Furukawa, et al., in U.S. Pat. No. 4,340,598, issued Jul. 20, 1982, discloses hypotensive imidazole derivatives of the formula: 
wherein R1 is lower alkyl or, phenyl C1-2 alkyl optionally substituted with halogen or nitro; R2 is lower alkyl, cycloalkyl or phenyl optionally substituted; one of R3 and R4 is xe2x80x94(CH2)nCOR5 where R5 is amino, lower
alkoxyl or hydroxyl and n is 0, 1, 2 and the other of R3 and R4 is hydrogen or halogen; provided that RI is lower alkyl or phenethyl when R3 is hydrogen, n=1 and R5 is lower alkoxyl or hydroxyl; and salts thereof.
Furukawa, et al., in EP 103,647 discloses 4-chloro-2-phenylimidazole-5-acetic acid derivatives useful for treating edema and hypertension of the formula: 
where R represents lower alkyl and salts thereof.
The metabolism and disposition of hypotensive agent 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid is disclosed by H. Torfii in Takeda Kenkyushoho, 41, No 3/4,180-191 (1982).
Frazee, et al., in EP 125,033-A discloses 1-phenyl(alkyl)-2-(alkyl)-thioimidazole derivatives which are inhibitors of dopamine-xcex2-hydroxylase and are useful as antihypertensives, diuretics and cardiotonics.
Published European Patent Application EP 146,228-A filed Oct. 16, 1984, by S. S. L. Parhi discloses a process for the preparation of 1-substituted-5-hydroxymethyl-2-mercaptoimidazoles.
A number of references disclose 1-benzyl-imidazoles such as U.S. Pat. No. 4,448,781 to Cross and Dickinson (issued May 15, 1984); U.S. Pat. No. 4,226,878 to Ilzuka, et al. (issued Oct. 7, 1980); U.S. Pat. No. 3,772,315 to Regel, et al. (issued Nov. 13, 1973); U.S. Pat. No. 4,379,927 to Vorbruggen, et al. (issued Apr. 12, 1983); amongst others.
Pals, et al., Circulation Research 29,673 (1971) describe the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone All to yield an (octa)peptide that blocks the effects of All on the blood pressure of pithed rats. This analog, [Sar1, Ala8] All, initially called xe2x80x9cP-113xe2x80x9d and subsequently xe2x80x9cSaralasin,xe2x80x9d was found to be one of the most potent competitive antagonists of the actions of All, although, like most of the so-called peptide-AII-antagonists, it also possesses agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating All (Pals et al., Circulation Research 29,673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B. V., p. 246 (1984). However, due to its agonistic character, Saralasin generally elicits, pressor effects when the pressure is not sustained by AII. Being a peptide, the pharmacological effects of saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
Currently there are several A II antagonists in development. Among these development candidates, is Losartan which is disclosed in a U.S. Pat. No. 5,138,069 issued to DuPont on Aug. 11, 1992. Losartan has been demonstrated to be an orally active A II antagonist, selective for the-AT1 receptor subtype.
Some known non-peptide antihypertensive agents act by inhibiting an enzyme, called angiotensin converting enzyme (ACE), which is responsible for conversion of angiotensin I to AIL Such agents are thus referred to as ACE inhibitors, or converting enzyme inhibitors (CEI""s). Captopril and enalapril are commercially available CEI""s.
Based on experimental and clinical evidence, about 40% of hypertensive patients are non-responsive to treatment with CEI""s. But when a diuretic such as furosemide or hydrochlorothiazide is given together with a CEI, the blood pressure of the majority of hypertensive patients is effectively normalized Diuretic treatment converts the non-renin dependent state in regulating blood pressure to a renin-dependent state. Although the imidazoles of this invention act by a different mechanism, i.e., by blocking the All receptor rather than by inhibiting the angiotensin converting enzyme, both mechanisms involve interference with the renin-angiotensin cascade. A combination of the CEI enalapril mialeate and the diruetic hydrochlorothiazide is commercially available under the trademark Vaseretic(copyright) from Merck and Co. Publications which relate to the use of diuretics with CEI""s to treat hypertension, in either a diuretic-first, stepwise approach or in physical combination, include Keeton, T. K. and Campbell, W. B., Pharmacol. Rev., 31:81 (1981) and Weinberger, M. H., Medical Clinics N. America, 71:979 (1987). Diuretics have also been administered in combination with saralasin to enhance the antihypertensive effect.
Non-steroidal anti-inflammatory drugs (NSAID""s) have been reported to induce renal failure in patients with renal under perfusion and high plasma level of All. (Dunn, M. J., Hospital Practice, 19-99, 1984). Administration of an AII blocking compound of this invention in combination with an NSAID (either stepwise or in physical combination) can prevent such renal failure. Saralasin has been shown to inhibit the renal vasoconstrictor effect of indomethacin and meclofenamate in dogs (Satoh, et al., Circ. Res. 36/37 (Suppl. 1): 1-89, 1975; Blasingham, et al., Am J. Physiol 239-(F360,1980). The CEI captopril has been demonstrated to reverse the renal vasoconstrictor effect of indomethacin in dogs with non-hypotensive hemorrhage. (Wong, er al., J. Pharmacol. Exp.Ther 219:104,1980).
Insulin resistance is defined as a reduced biological effect of insulin, and has been shown to be an independent risk factor for cardiovascular disease, and to be associated with hypertension, obesity and diabetes. Modan M, Halkin H, Almog S., et al.: Hyperinsulineamia: a link between hypertension, obesity and glucose intolerance. J. Clin Invest 1985, 75:809-817; Landberg L: Diet, obesity, and hypertension: an hypothesis involving insulin, the sympathetic nervous system, and adaptive thermogenesis. Q. J. Med. 1986, 236: 1081-1090; Ferranini E, Buzzigoli G, Giorico M A., et al.: Insulin resistance in essential hypertension. 9. Engl. J. Med. 1987, 317:350-357.
Pharmacological treatment of hypertension has reduced the incidence of stroke to the level expected from epidemiological studies, but has shown considerably less of an effect on coronary heart disease. Collins R., Peto R., MacMahon, S., Hebert P. Fiebach N. H., Eberlein K. A., et al. xe2x80x9cBlood Pressure, Stroke and Coronary Heart Disease. Part 2, short term reductions in Blood pressure: overview of randomized drug trials in their epidemiological context.xe2x80x9d Lancet 1990; 9: 983-986. The reason for this is unclear, but one of the, possible explanations is the use of beta-blockers and diuretics negatively influence lipid balance and insulin sensitivity. Studies of other vasodilatatory drugs, such as calcium-channel blockers, ACE-inhibitors and alpha-blockers, these drugs have been found to be neutral or improve insulin resistance. A mechanism has been suggested by Julius S. Gudbrandsson T, Jamerson. K et al., xe2x80x9cThe hemodynamic link between insulin resistance and hypertension.xe2x80x9d J. Hypertens 1991; 9:983-986 and others, that it is possibly a hemodynamic determinator of insulin resistance.
The use for the preparation of drugs for and a method of increasing the survival rate of transplant patients, including renal and heart transplant patients, of a therapeutically effective amounts of an angiotensin II receptor antagonist compound of formula I: 
wherein:
R1 is: 
R2 is H; Cl; Br; I; F; NO2; CN; alkyl of 1 to 4 carbon atoms; acyloxy of 1 to 4 carbon atoms; alkoxy of 1 to 4 carbon atoms; CO2H; CO2R9; HNSO2CH3; NHSO2CF3; CONHOR12; SO2NH2; 
xe2x80x83aryl; or furyl;
R3 is H; Cl, Br, I or F; alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
R4 is CN, NO2 or CO2R11;
R5 is H; alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms;
R6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO2RI4; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl, of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl 5 to 10 carbon atoms; (CH2)sZ(CH2)mR5 optionally substituted with F or CO2R14; benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;
R7 is Hxe2x88x92; F, Cl, Br, I, NO2, CvF2v+1, where v=1-6, C6F5; CN; 
straight or branched alkyl of 1 to 6 carbon atoms; phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms; or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH3, CF3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl;
R8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; xe2x80x94(CH2)m-imidazole-1-yl; xe2x80x94(CH2)m-1,2,3-triazolyl optionally substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms; (CH2)s tetrazolyl; 
R10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH2)pC6H5;
R11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R12 is H, methyl or benzyl; 
R14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;
R16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH2)pC6H5, OR17, or NR18R19;
R17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R18 and R19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, xcex1-methylbenzyl, or taken together with the nitrogen form a ring of the formula 
Q is N20, O or CH2;
R20 is H, alkyl of 1-4 carbon atoms, or phenyl;
R21 is of 1 to 6 carbon atoms, xe2x80x94NR22R23, or 
R22 and R23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH2)u, where u is 3-6;
R24 is H, CH3 or xe2x80x94C6H5;
R25 is NR27R28, OR28, NHCONH2, NHCSNH2, 
R26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
R27 and R28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R29 and R30 are independently alkyl of 1-4 carbon atoms or taken together are xe2x80x94(CH2)qxe2x80x94;
R31 is H, alkyl or 1 to 4 carbon atoms, xe2x80x94CH2CHxe2x95x90CH2 or CH2C6H4R32;
X is a carbonxe2x80x94carbon single bond, 
Y is O or S;
Z is O, NR11, or S;
m is 1 to 5;
n is 1 to 10;
p is 0 to 3;
q is 2 to 3;
r is 0 to 2;
s is 0 to 5;
and pharmaceutically acceptable salts of these compounds;
provided that:
(1) the R1 group is not in the ortho position.
(2) when R1 is 
X is a single bond, and R13 is CO2H, or 
then R13 must be in the ortho or meta position; or
when R1 and X are as above and R13 is NHSO2CF3 or NHSO2CH3, R13 must be ortho;
(3) when R1 is 
and X is other than a single bond, then R13 must be ortho except when X=NR23CO and R13 is NHSO2CF3 or NHSO2CH3, then R13 must be ortho or meta;
(4) when, R1 is 4-CO2H or a salt thereof, R6 cannot be 8-alkyl;
(5) when R1 is 4-CO2H or a salt thereof, the substituent on the 4-position of the imidazule cannot be CH2OH, CH2OCOCH3, or CH2CO2H;
(6) when R1 is 
X is xe2x80x94OCH2xe2x80x94, and R13 is 2-CO2H, and R7 is H then R6 is not C2H5S;
(7) when R1 is 
and R6 is n-hexyl then R7 and R8 are not both hydrogen;
(7) when R1 is 
R6 is not methoxybenzyl;
(9) the R6 group is not 
xe2x80x83or CH2OH;
(10) When r=0, R1 is 
X is 
xe2x80x83R13 is 2-NHSO2CF3, and R6 is n-propyl, then
R7 and R8 are not xe2x80x94CO2CH3;
(11) when r=0, R1 is: 
X is 
R13 is 2-COOH, and R6 is n-propyl; then R7 and R8 are not xe2x80x94CO2CH3;
(12) when r=1, R1 is: 
X is a single bond, R7 is Cl, and R8 is xe2x80x94CHO, then
R13 is not 3-(tetrazol-5-yl).
(13) when r=1, R1 is: 
X is a single bond, R7 is Cl, and R8 is xe2x80x94CHO, then
R13 is not 4-(tetrazol-5-yl).
The following variations of the invention also form an object of the present invention.
The use for the preparation of drugs and a method for treating and preventing chronic rejection in renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula I as above.
The use for the preparation of drugs and a method for reducing proteinuria in renal transplant, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula I as recited above.
The use for the preparation of drugs and a method for treating post-transplant hypertension in renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula I as above.
An embodiment of the invention is the use for the preparation of drugs and a method for increasing the survival rate of transplant patients, including renal and heart transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula II: 
wherein:
R1 is CO2H; xe2x80x94NS2CF3; 
R6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, benzyl substituted on the phenyl ring with up to two groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro;
R8 is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbon atoms, xe2x80x94(CH2)m-imidazol-1yl, xe2x80x94(CH2)m 1,2,3-triazolyl optionally substituted with one or two groups selected from CO2CH3 or alkyl of 1 to 4 carbon atoms, 
R13 is xe2x80x94CO2H, xe2x80x94CO2R9, NHSO2CF3; SO3H; 
R16 is H, alkyl of 1 to 5 carbon atoms, OR17, or NR18R19;
X is carbonxe2x80x94carbon single bond, xe2x80x94COxe2x80x94, 
xe2x80x83xe2x80x94CH2CH2xe2x80x94, 
xe2x80x83xe2x80x94OCH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94NHCH2xe2x80x94, xe2x80x94CH2NHxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94; and pharmaceutically acceptable salts of these compounds.
An embodiment of the invention is the use for the preparation of drugs and a method for treating and preventing chronic rejection in. renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula II as recited above.
An embodiment of the invention is the use for the preparation of drugs and a method for reducing proteinuria in renal transplant, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula II as recited above.
An embodiment of the invention is the use for the preparation of drugs and a method for treating
post-transplant hypertension in renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula II as recited above.
A preferred embodiment of the invention is the use for the preparation of drugs ans a mehod for increasing the survival rate of transplant patients, including renal and heart transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula III: 
wherein:
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;
R6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;
R7 is H, Cl, Br, CxcexdF2xcexd+1, where v=1-3, 
R10 is CF3, alkyl of 1 to 6 carbon atoms or phenyl;
R11 is H, or alkyl of 1 to 4 carbon atoms;
R13 is CO2H; CO2CH2OCOC(CH3)3; NHSO2CF3; 
R14 is H, or alkyl of 1 to 4 carbon atoms;
R15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;
R16 is H, alkyl of 1 to 5 carbon atoms; OR17; or 
m is 1 to 5
X is single bond; xe2x80x94Oxe2x80x94; xe2x80x94COxe2x80x94; NHCOxe2x80x94; or xe2x80x94OCH2xe2x80x94;
and pharmaceutically acceptable salts thereof.
An embodiment of the invention is the use for the preparation of drugs and a method for treating and preventing chronic rejection in renal transplant patients using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula III as recited above.
An embodiment of the invention is the use for the preparation of drugs and a method for reducing proteinuria in renal transplant using a therapeutically effective amount of an angintensin II receptor antagonist compound of formula III as recited above.
An embidoment of the invention is the use for the preparation of drugs and a method for treating post-transplant hypertension in renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound of formula III as recited above.
A more preferred embodiment of the invention is the use for the preparation of drugs nd a method for increasing the survival rate of transplant patients, including renal and heart transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist selected from the group consisting of:
2-Butyl-4-chloro-1-[(2xe2x80x2-(1H-tetrazol-Syl).yl)biphenyl-4yl)methyl]-5-(hydroxymethyl) imidazole;
2-butyl-4-chloro-1-[(2xe2x80x2-carboxybiphenyl-4-yl)methyl)-5-(hydroxy-methyl) imidazole
2-Butyl-4-chloro-1-[(2xe2x80x2-carboxybiphenyl-4-yl)methyl]-5-L(methoxy-carbonyl)aminomethyl]imidazole
2-Butyl-4-chloro-1-[(2-carboxybiphenil-4-yl)methyl]-5-[(propoxy-carbonyl)aminomethyl]imidazole
2-Butyl-4-chloro-1-[(2xe2x80x2-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde;
2-Butyl-1-[(2xe2x80x2-carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde;
2-(1E-Butenyl)-4-chloro-1-[(2xe2x80x2-carboxybiphenyl-4-yl)methyl]-5(hydroxymethyl)imidazole;
2-(1E-Butenyl)-4-chloro-1-[(2xe2x80x2-carboxybiphenyl-4-yl)methyl]-imidazole 5-carboxaldehyde;
2-Propyl-1-chloro-1-[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl) imidazole;
2-Propyl-4-chloro-1[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde;
2-Butyl-4-chloro-1-[2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl) methyl]-imidazole-5-carboxaldehyde;
2-(1E-Butenyl)-4-chloro-1-[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-hydroxymethyl) imidazole;
2-(1E-Butenyl)-4-chloro-1-[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde;
2-Butyl-4-chloro-1-[(2xe2x80x2-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid;
2-Propyl-4-chloro-1-[(2xe2x80x2-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid;
2-Propyl-4-trifluoromethyl-1-[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid;
2-Propyl-4-trifluoromethyl-1-[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxylmethyl)imidazole;
2-Butyl-4-trifluoromethyl-1-[2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid;
2-Propyl-4-trifluoromethyl-1-[(2xe2x80x2-(carboxybiphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde;
2-Propyl-4-pentafluoroethyl-1-[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)imidazole;
2-Propyl-1-[(2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-4,5,-dicarboxylic acid;
2-Propyl-4-pentafluoroethyl-1-[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid;
2-Propyl-4-pentafluoroethyl-[(2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde; and
or a pharmaceutically acceptable salt thereof.
A more preferred embodiment of the invention is the use for the preparation of drugs and a method for treating and preventing chronic rejection in renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound to as recited above.
A more preferred embodiment of the invention is the use for the preparation of drugs and a method for reducing proteinuria in renal transplant, using a therapeutically effective amount of an angiotensin II receptor antagonist as recited above.
A more preferred embodiment of the invention is the use for the preparation of drugs and a method for treating post-transplant hypertension in renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist as recited above.
A most preferred embodiment of the invention is the use for the preparation of drugs and a mehtod for increasing the survival rate of transplant patients, including renal and heart transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist selected from the group consisting of:
2-Butyl-4-chloro-1-[(2xe2x80x2-tetrazol-5-yl)biphenyl-4-yl]methyl3-5-(hydroxy-methyl) imidazole; and
2-Butyl-4-chloro-1-[(2xe2x80x2-tetrazol-5-yl)biphenyl-4-yl]methylimidazole-5-carboxylic acid or a pharmaceutically acceptable salt thereof.
A most preferred embodiment of the invention is the use for the preparation of drugs and a method for treating and preventing chronic rejection in renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist compound as recited above.
A most preferred embodiment of the invention is the use for the preparation of drugs and a method for reducing proteinuria in renal transplant, of a therapeutically effective amount of an angiotensin II receptor antagonist as recited above.
A most preferred embodiment of the invention is the use for the preparation of drugs and a method for treating post-transplant hypertension in renal transplant patients, using a therapeutically effective amount of an angiotensin II receptor antagonist as recited above.
Note that throughout the text when an alkyl substituent is mentioned, the normal alkyl structure is meant (i.e., butyl is n-butyl) unless otherwise specified.
Pharmaceutically suitable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington""s Pharmaceutical Sciences 1-7th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydro-scopicity and solubility. Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium, and ammonium salts.
It should be noted in the foregoing structural formula, when a radical can be a substituent in more than one previously defined radical, that first radical can be selected independently in each previously defined radical. For example, R1, R2 and R3 can each be CONHOR12. R12 need not be the same substituent in. each of R1, R2 and R3 but can be selected independently for each of them.
The novel compounds of Formula (1) may be prepared using the reactions and techniques described in U.S. Pat. No. 5,138,069 and WO 93/10106 or one of its three U.S. counterparts, U.S. Pat. No. 5,130,439issued Jul. 14, 1992, U.S. Pat No. 5,206,374 issued Apr. 27, 1993, and U.S. Ser. No. 07/911,813 filed Jul. 10, 1992.